Asymmetric synthesis of optically active compounds

ABSTRACT

Asymmetric synthesis of optically active 3,7,11-trimethyl-dodecan-1-ol, an intermediate for producing optically active vitamin E, from isovaleraldehyde or prenal including intermediates in this synthesis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is related to U.S. Pat. Application Ser. No. 417,465,filed Nov. 19, 1973 now U.S. Pat. No. 3,947,473, Scott, Parrish andSaucy, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

In the past, optically active α-tocopherol and derivatives thereof whichare the 2R, 4'R, 8'R isomers of compounds of the formula: ##STR1## havebeen prepared through isolation from natural sources such as vegetableoil. This procedure suffers from many drawbacks due to the fact that thetocopherol content of these oils is very small. Therefore, a greatamount of oil must be processed in order to isolate a small amount ofnatural tocopherol. Additionally, the process whereby varioustocopherols are isolated from vegetable oil is extremely cumbersome.

In U.S. Pat. application Ser. No. 417,465, filed Nov. 19, 1973, Scott etal., natural α-tocopherol has been synthesized by reacting via a Wittigreaction a compound of the formula: ##STR2##

wherein R taken together with its attached oxygen atom forms an ether orester protecting group removable by hydrogenation or hydrolysis. (Pleasenot the compound of formula XXVII-A in U.S. application Ser. No.417,465, filed Nov. 19, 1973) with a dodecanol of the formula: ##STR3##(Please note compound XLVIII-B in U.S. application Ser. No. 417,465). Adisadvantage of this process is that the dodecanol of formula III hasbeen difficult to synthesize asymmetrically. In the past, this dodecanolhas been produced through degradation 1973) naturally occurringmaterials such as phytol.

SUMMARY OF THE INVENTION

In accordance with this invention, there is provided a procedure forasymmetrically synthesizing the optically active compound of formula IIIfrom isovalderaldehyde or prenal without the need for separating anddiscarding any unwanted optical isomer. Therefore, in accordance withthe process of this invention, the total quantity of isovaleraldehyde orprenal utilized as a starting material is converted to the opticallyactive isomer of formula III and finally to natural α-tocopherol.

The new asymmetric synthesis is achieved in accordance with thisinvention by the discovery that when a compound of the formula: ##STR4##

wherein A and B individually are hydrogen or taken together to form acarbon to carbon bond; one of R₁ and R₂ is hydroxy and the other ishydrogen; n is an integer of from 0 to 1 with the proviso that when R₁is hydrogen, the 2-3 double bond has a trans configuration and when R₁is hydroxy the 2-3 double bond has a cis configuration;

is subjected to Claisen rearrangement, an optically active compound ofthe formula: ##STR5##

wherein R₆ is lower alkoxy, hydrogen, ##STR6## are lower alkyl; and Aand B are as above; is formed which can be directly converted into theoptically active compound of formula III.

In accordance with this invention, the compound of formula IV can beeither a compound of the formula: ##STR7##

wherein A and B are as above; R₁ and R₂ are as above with the provisothat when R₁ is hydrogen, the 2-3 double bond has a trans configurationand that when R₁ is hydroxy, the 2-3 double bond has a cisconfiguration;

or a compound of the formula: ##STR8##

wherein R₁ and R₂, A and B are as above and with the proviso that whenR₁ is hydrogen, the 2-3 double bond has a trans configuration and thatwhen R₁ is hydroxy, the 2-3 double bond has a cis configuration. Thecompound of formula IV-A when subjected to Claisen rearrangement,produces a compound of the formula: ##STR9##

wherein A, B and R₆ are as above. The compound of formula IV-B whensubjected to Claisen rearrangement, produces a compound of the formula:##STR10##

wherein R₆, A and B are as above.

DETAILED DESCRIPTION OF THE INVENTION

The numbering of the chain in formula I, III, and V above, is shown forthe purpose of convenience.

As used throughout the application, the term "lower alkyl" comprehendsboth straight and branched chain saturated hydrocarbon groups containingfrom 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, etc.As used throughout this application, the term "halogen" includes allfour halogens, such as bromine, chlorine, fluorine and iodine. The term"alkali metal" includes sodium, potassium, lithium, etc.

When the term "cis" is utilized in this application, it designates thatthe two largest substituents attached across the double bond are on thesame side of the double bond. The term "trans" as utilized in thisapplication, designates that the largest substituents attached acrossthe double bond are on opposite sides of the double bond.

In the pictorial representation of the compounds given throughout thisapplication, a tapered line indicates a substituent which is pointed outof the plane of the paper towards the reader.

The term "lower alkoxy" as used throughout the specification denoteslower alkoxy groups containing from 1 to 7 carbon atoms such as methoxy,ethoxy, propoxy, isopropoxy, etc. The term "lower alkanoyl" as usedthroughout the specification denotes lower alkanoyl groups containingfrom 2 to 6 carbon atoms such as acetyl or propionyl.

In accordance with this invention, isovaleraldehyde or prenal isconverted to the compound of formula V-A via the followingintermediates: ##STR11##

wherein A and B and R₆ are above; M is an alkali metal; R₃ is a radicalderived from a dicarboxylic acid by removal of the hydroxy moiety of oneof the carboxylic acid groups; R₅ is hydrogen, lower alkoxy, ##STR12##

and R₉ are as above: Δ designates that the double bond has a cisconfiguration and Δ' designates that the double bond has a transconfiguration.

In the first step of this invention, isovaleraldehyde or prenal, i.e., acompound of the formula: ##STR13## is converted to the compound offormula VII by reacting isovaleraldehyde or prenal with a compound ofthe formula:

    CH.sub.3 - C .tbd.C - MgX                                  XIII

wherein X is a halogen;

via a Grignard reaction. Any of the conditions conventional in Grignardreactions can be utilized to carry out this conversion.

The compound of formula VII can be resolved to its optical antopodes offormula VII-A and VII-B through the reaction of the compound of formulaVII with a dicarboxylic acid to form a half ester and the reaction ofthe half ester with an optically active base. In forming the half ester,i.e., the compound of formula VIII any conventional dicarboxylic acidcan be utilized. Among the preferred dicarboxylic acids are includedlower alkyl dicarboyxlic acids such as oxalic acid, malonic acid,succinic acid, glutamic acid, adipic acid or aromatic carboxylic acidssuch as the phenyl dicarboxylic acids which include phthalic acid. Theformation of the half ester is carried out by conventional means such asreacting the compound of formula VII with the dicarboxylic acid or anactive derivative of the dicarboxylic acid such as the anhydridethereof. This esterification generally takes place in the presence of anorganic amine base. Any conventional organic amine base such as pyridineand lower alkyl amines can be utilized. Where the organic amine base isa liquid such as pyridine, this base can be utilized as the inertsolvent medium. On the other hand, any conventional inert organicsolvent can be utilized in forming the half ester. In forming this halfester, temperature and pressure are not critical and this half ester canbe formed at room temperature and atmospheric pressure. On the otherhand, elevated or reduced temperatures and pressures can be utilized.

The half ester of formula VIII is then reacted with an optically activeorganic amine base such as brucine, ephedrine or quinine to produce thediastereomeric salt of the formula: ##STR14##

wherein R₂₀ is a divalent phenyl or lower alkyl radical and R₂₁ is anoptically active organo radical. Any conventional optically activeorgano amine base can be utilized to form the compound of formulaVIII-C. Among the preferred bases are those mentioned above as well asdehydroabiethylamine, alpha-methyl benzyl amine and alpha methyl-p-nitrobenzylamine. This reaction of the half ester of formula VIII with theorgano amine base can be carried out in any inert organic solventmedium. Among the preferred solvents are included the ether solventssuch as diethyl ether, dioxane, diglyme, tetrahydrofuran, etc. Incarrying out this reaction, temperature and pressure are not criticaland this reaction can be carried out at room temperature and atmosphericpressure. In this reaction, the optically active amine forms a salt withthe same optical isomer of the half ester of formula VIII. This saltprecipitates in solution leaving the other enantiomer of the compound offormula VIII in solution. After separating the crystallized salt fromthe reaction medium, the antipode of the optically active amine usedpreviously is reacted with the other enantiomer of the half ester of thecompound of the formula VIII. This reaction is carried out in the samemanner as with the reaction of the first enantiomer with the opticallyactive amine. Upon reaction, the salt crystallizes from the organicsolvent medium.

The respective enantiomeric salts of formula VIII-C are converted byacidification to the compounds of formula VII-A and VIII-B afterseparation. Any conventional method of acidification can be utilized tocleave the separated antipodes of the compound of formula VIII-C to formthe corresponding compound of formula VIII-A and VIII-B. Among thepreferred methods is to treat the compound of formula VIII-C with aninorganic acid. Among the preferred inorganic acids are includedsulfuric acid, phosphoric acid, hydrohalic acids such as hydrochloric,etc. This reaction is carried out at room temperature and atmosphericpressure. In carrying out this reaction, it is generally preferred toutilize an aqueous medium. Hence, this reaction is generally carried outin water. The acidification takes place in the aqueous medium at a pH offrom 0.1 to 4 by the addition of acid.

The compounds of formula VIII-A and VIII-B are converted into thecompounds of the formula VII-A and VII-B respectively. This conversionis generally carried out by ester hydrolysis. Any conventional method ofester hydrolysis can be utilized to carry out this conversion. Apreferred method is carrying out this reaction in the presence of a basesuch as an alkali metal hydroxide base in an aqueous medium.

The compound of formula VII-A is converted to the compound of theformula IX-A by hydrogenation in the presence of a selectivehydrogenation catalyst. Any conventional catalyst which selectivelyreduces only the triple bond (acetylene linkage) to a double bond can beutilized in carrying out this conversion. Among the preferred selectivehydrogenation catalysts are the palladium catalysts which contain adeactivating material such as lead, lead oxide or sulfur. Among thepreferred selective hydrogenation catalysts are included thepalladium-lead catalysts of the type disclosed in Helvetica ChemicaActa., 35 pg. 446 (1952) and U.S. Pat. No. 2,681,938 -Lindlar. Incarrying out this hydrogenation, temperature is not critical and thisreaction can be carried out at room temperature. On the other hand,elevated or reduced temperature can be utilized. Generally, thisreaction is carried out in an inert organic solvent. Any conventionalinert organic solvent can be utilized such as n-hexane, ethyl acetate,toluene, petroleum ether or methanol. The selective hydrogenation of acompound of the formula VII-A utilizing a selective hydrogenationcatalyst produces a cis configuration across the double bond formedthereby. Therefore, the subjection of a compound of the formula VII-A tocatalytic hydrogenation produces a compound of the formula IX-A wherethe double bond formed by the selective hydrogenation has a cisconfiguration.

In accordance with this invention, the compound of formula VII-B isconverted to the compound of formula IX-B by chemical reduction witheither sodium in liquid ammonia or an aluminum hydride reducing agent.The chemical reduction of the compound of formula VII-B reduces thetriple bond to a double bond which has a trans configuration. Hence, thecompound of formula IX-B is formed by this chemical reduction with thedouble bond having a trans configuration. Where the reduction is carriedout utilizing sodium liquid ammonia, any of the conditions conventionalin this type of reduction can be utilized. Generally, this reaction iscarried out at a temperature of from about -30° C. to -80° C. In thisreduction, the liquid ammonia can be utilized as the reaction medium. Onthe other hand, a co-solvent can be present in the reaction medium alongwith liquid ammonia. As the co-solvents, any conventional inert organicsolvent which is in liquid form at the temperature of the reaction canbe utilized. Among the preferred inert organic solvents are includedether solvent such as diethyl ether, tetrahydrofuran, etc. On the otherhand, the reduction can be carried out by treating the compound offormula VII-B with an aluminum hydride reducing agent. Any conventionalaluminum hydride reducing agent can be utilized to carry out thisreduction. Among the preferred reducing agents are the alkyl aluminumhydrides reducing agents such as diisobutyl aluminum hydride, diisoamylaluminum hydride, etc. as well as sodium bis-[2-methoxyethoxy]-aluminumhydride. The reduction with an aluminum hydride reducing agent iscarried out in an inert organic solvent medium. Any conventional inertorganic solvent medium can be utilized for carrying out this reaction.Among the preferred inert organic solvents included tetrahydrofuran,pentane, dioxane, diethyl ether, hexane, toluene, benzene or xylene.Generally, temperatures of from about -120° C. to about 140° C. areutilized in carrying out this reduction reaction.

In accordance with this invention, when the compound of formula IX-A orIX-B is subjected to Claisen rearrangement, the compound of formula V-Ais produced. In accordance with this invention, it has been found thatboth of the compounds of formula IX-A and IX-B undergo Claisenrearrangement to produce the compound of formula V-A. The compound offormula IX-A is converted to the compound of formula V-A via anintermediate of the formula XI-A and the compound of formula IX-B isconverted to the compound of formula V-A via an intermediate of theformula XI-B. Any of the conditions conventional in Claisenrearrangement can be utilized in carrying out the conversion of eitherthe compound formed by the compound of the formula IX-A or IX-B to acompound of the formula V-A. It is known that Claisen rearrangementsoccur asymetrically. See Hill, et al., J. Org. Chem., Vol. 37, No. 32,1972, pages 3737-3740, as well as Sucrow et al. Chem. Ber., 104,3689-3703 (1971), and Sucrow & Richter, Chem. Ber., 140, 3679-3688(1971). However, in the substrates utilized as starting materials in theClaisen rearrangements disclosed by Hill, asymmetric induction dependsupon the presence of the optically active asymmetric carbon atom in thestarting material. On the other hand, in accordance with this invention,in order to obtain by asymmetric induction through the Claisenrearrangement the desired isomer which can be converted to opticallyactive natural vitamin E, both the proper optical configuration aboutthe asymmetric carbon atom and the proper geometric configuration aboutthe double bond must be present in the starting material. If thecompound of the formula IX-A or IX-B is utilized in the form of amixture of optical isomers or geometric isomers or both, one will notobtain the proper asymmetric induction through the Claisen rearrangementreaction to produce the intermediate of formula V-A which can beconverted directly to optically active natural vitamin E.

The compounds of formula IX-A and IX-B are converted via the Claisenreaction to the compound of formula V-A via the intermediates in theformula XI-A and XI-B. In carrying out this reaction, any of theconditions conventionally utilized in Claisen type rearrangementreaction such as described in the above publications can be utilized. Inaccordance with the preferred embodiment of this invention, the Claisenrearrangement is carried out by reacting the compounds of formula IX-Aor IX-B with any one of the following reactants: ##STR15##

wherein R₇ and R₈ are as above, and R₁₀ is lower alkyl, and X ishalogen.

The compound of formula V-A where R₆ is hydrogen can be formed byreacting either the compound of formula IX-A or IX-B with the vinylether of formula XV-A via a Claisen rearrangement reaction. Any of theconditions conventional in carrying out a Claisen rearrangement with avinyl ether can be utilized in carrying out this reaction. Where thecompound of formula IX-A is utilized, the compound of formula IX-A whereR₅ is hydrogen is formed as an intermediate. On the other hand, wherethe compound of formula IX-B is utilized as the starting material, thecompound of the formula XI-B where R₅ is hydrogen is formed as anintermediate. In converting the compound of formula IX-A and IX-B to thecompound of formula XI-A and XI-B respectively, the compound of formulaIX-A or IX-B is first reacted with the vinyl ether of formula XV-A. Inreacting either the compound of the formula IX-A or IX-B with thecompound of formula XV-A to form the compound of formula XI-A and XI-Bwhere R₅ is hydrogen, temperatures of from about 40° C. to 150° C. aregenerally utilized. This reaction takes place in the presence of an acidcatalyst. Any conventional acid catalyst can be utilized. Among thepreferred acid catalysts are the inorganic acids such as phosphoric acidand the hydrohalic acids as well as acid salts such as mercuric acetate.On the other hand, conventional organic acid catalysts such as p-toluenesulfonic acid and p-nitrophenol can be utilized. This reaction can becarried out in an inert organic solvent. Any conventional inert organicsolvent having a boiling point of greater than 40° C. can be utilized.Among the preferred solvents are the high boiling hydrocarbon solventssuch as benzene, toluene, xylene, heptane, as well as ether solventssuch as dimethoxyethane, diethylene glycol-dimethyl ether and dioxane.The compound of formula XI-A or XI-B where R₅ is hydrogen can beconverted to the compound of formula V-A where R₆ is hydrogen by heatingto a temperature of from 80° C. to 200° C. This reaction is carried outin the absence of any catalyst. However, the same solvent mediumutilized for forming the compounds of formulas XI-A or XI-B can beutilized in carrying out this reaction.

On the other hand, the compounds of formula IX-A and IX-B can beconverted to the compound of formula V-A utilizing the orthoacetate offormula XV-B. In carrying out this reaction, any of the conditionsconventionally used in Claisen rearrangements with this orthoacetate canbe utilized. Where the compound of formula IX-A is utilized, thecompound of formula XI-A where R₅ is lower alkoxy forms as anintermediate. On the other hand, where the compound of formula IX-B isutilized, the compound of formula XI-B forms as an intermediate. Underthe conditions of this reaction, the compound of formula XI-A and thecompound of formula XI-B where R₅ is lower alkoxy rearrangesinstantaneously to produce the compound of the formula V-A where R₆ islower alkoxy. In carrying out this reaction, temperatures of from 140°C. are generally utilized. This reaction is carried out in the presenceof excess of the orthoacetate of formula XV-B. This is true since theorthoacetate can be utilized as the solvent medium. On the other hand,the reaction takes place in an inert organic solvent, generally thosesolvents having a boiling point of greater than 140° C. are preferred.Generally it is preferred to carry out this reaction in the presence ofa lower alkanoic acid. If desired, the lower alkanoic acid is present inmolar amounts of from about 1 to 10% per mole of the compound of formulaIX-A or IX-B utilized as the starting material.

Where it is desired to produce the compound of formula V-A where R₆##STR16## the compounds of formula IX-A and IX-B are first converted tothe compounds of formula X-A and X-B respectively via acetylation withan acetic acid or reactive derivatives thereof. Any conventional methodof esterifying a hydroxy group with an acetyl group can be utilized tocarry out this conversion. Among the preferred methods is to react thecompound of formula X-A or X-B with a reactive derivative of an aceticacid such as a halide derivative or an anhydride derivative. Thecompounds of formula X-A and X-B in their enolate form are then reactedwith a compound of the formula XV-E to form the compound of the formulaV-A via a Claisen reaction. The enolates of the compound of formula X-Aand X-B which are the compounds of formula X-A₁ and X-B₁ are produced byreacting the compounds of formula X-A and X-B respectively with analkali metal alkyl amide base. Any conventional alkali metal aklyl amidecan be utilized. The alkyl moiety can be a lower alkyl or cycloalkylmoiety which contains from 5 to 7 carbon atoms. Among the preferredbases are lithium isopropyl cyclohexyl amide and lithium diisopropylamide. Upon reaction of the enolate of formula X-A₁ and X-B₁ with thesilyl halide of formula XV-E, compounds of the formula XI-A or XI-Bform, where ##STR17## as intermediates. This reaction takes placeutilizing the conditions conventional in Claisen type reactions withalkyl silyl halides. Generally, the enolates of formula X-A₁ or X-B₁ arereacted with the silyl halide in an inert organic solvent medium at atemperature of from -10° C. to -110° C. In carrying out this reaction,any conventional inert organic solvent which will not freeze at thereaction temperature can be utilized. Among the preferred solvents aretetrahydrofuran and diethyl ether.

The compounds of formula XI-A and XI-B where R₅ is ##STR18## areconverted to the corresponding compound of formula V-A by warming eitherthe compound of formula XI-A or XI-B in the reaction mixture in whichthey were formed to a temperature of from 0° to 40° C. Therefore, inaccordance with this invention, there is no need to isolate thecompounds of formula XI-A and XI-B from their reaction mixture. Thereaction mixture containing the compounds of formula XI-A and XI-B canbe warmed to a temperature of from 0° to 40° C. to form the compound offormula V-A. On the other hand, the compound of formula XI-A and XI-Bcan be isolated from the reaction mixture before warming has commenced.

Where it is desired to produce the compound of formula XII where R₆##STR19## the compounds of formula IX-A and IX-B are converted to thecompound of formula XI-A and XI-B where ##STR20## by conventionalClaisen reaction utilizing conditions conventional in Claisen reactionswith amides of either formulas XV-C or XV-D or mixtures thereof. In thisreaction, the compounds of formula XI-B and XI-A where ##STR21## form asintermediates. This reaction is instantaneously converted under theconditions of the reaction to the compound of formula V-A. This reactionis carried out by reacting compounds of formula X-A and X-B with acompound of the formula XV-C or XV-D or mixtures thereof. This reactionis carried out at temperatures of from 120° C. to 250° C. in an inertorganic solvent. Any conventional inert organic solvent can be utilizedto carry out this reaction with high boiling solvents, i.e., solventsbeing above 120° C. being preferably utilized. Among the conventionalinert organic solvents are included xylene and diglyme.

Where R₆ in the compound of formula V-A is other than hydrogen, thecompound of formula V-A can be converted to the compound of the formula:##STR22## by hydrolysis by hydrolyzing the ester or amide group. Anyconventional method of ester or amide hydrolysis can be utilized toaffect this conversion. The silyl esters are also hydrolyzed to thecompound of formula VI by conventional means. On the other hand, whereR₆ in the compound of formula V-A is hydrogen, the aldehyde can beconverted to the compound of the formula VI by oxidizing with aconventional oxidizing agent.

Any of the conventional oxidizing agents can be utilized. Among thepreferred oxidizing agents are magnesium dioxide, silver oxide andchromic oxide. Any of the conditions conventional in utilizing theseoxidizing agents can be utilized to convert the aldehyde of formula V tothe compound of formula VI.

The compound of formula VI can be converted into compounds of theformula: ##STR23## by hydrogenation utilizing a metal hydrogenationcatalyst.

On the other hand, the compound of formula V-A can be converted to besaturated compound having the formula: ##STR24## by hydrogenation, whereR₆ is as above.

Any conventional hydrogenation procedure and metal hydrogenationcatalyst can be utilized to carry out this procedure. Among theconventional metal hydrogenation catalysts are included palladium andplatinum and Rainey nickel. After hydrogenation, the resulting compoundof formula XVII is subjected to hydrolysis where R₆ is lower alkoxy-##STR25## or oxidation where R₆ is hydrogen. Any conventional means ofester or amide hydrolysis can be utilized to carry out this conversion.Any conventional method of oxidizing aldehydes to carboxylic acids canbe utilized in this procedure for oxidizing the compound of the formulaXVII where R₆ is hydrogen.

The compound of formula XVI and the known compound of the formula##STR26## taken together as a starting material for the compound offormula III have the formula: ##STR27##

wherein A and B are as above. The compounds of formula XVI-A can beconverted into compounds of the formula III via the followingintermediates: ##STR28##

wherein A, B, M, R₅, R₆ are as above; Δ designates that the double bondhas a cis configuration; Δ ' designates that the double bond has a transconfiguration; R₁₂ is ##STR29## R₃ ' is hydrogen or a radical derivedfrom a monocarboxylic acid by removal of the hydroxy moiety from theacid group.

The compound of formula XVI-A can be converted into the compound of theformula XVIII by first reducing the compound of formula XVI-A to thealcohol of formula XVIII. This reduction can be carried out by utilizingan aluminum hydride reducing agent. In utilizing an aluminum hydridereducing agent, any conventional aluminum hydride reducing agent can beutilized. Among the aluminum hydride reducing agents which can beutilized are included lithium aluminum hydride, sodium aluminum hydride,diisobutyl aluminum hydride, disopropyl aluminum hydride, and sodiumbis[2-methoxyethoxy]-aluminum hydride. This reduction is carried out inan inert organic solvent medium. Any conventional inert organic solventcan be utilized in carrying out this reaction. Among the preferred inertorganic solvents are included tetrahydrofuran, dioxane, diethyl ether,hexane, toluene, benzene or xylene. This reaction can be carried out atroom temperature, i.e., 25° C. and atmospheric pressure. On the otherhand, reduced or elevated temperatures can be utilized, i.e. from -30°C. to about 140° C., with temperatures of from 25° C. to 60° C. beingpreferred.

The alcohol of formula XVIII can be oxidized to the aldehyde of formulaXIX utilizing conventional procedures for oxidizing alcohols toaldehydes. Any of the procedures conventional in oxidizing alcohols toaldehydes can be utilized in carrying out this conversion. Among thepreferred methods is utilizing an oxidizing agent such as chromic oxide,silver carbonate, chlorine in dimethylsulfoxide,dicyclohexylcarbodiimide in dimethylsulfoxide, etc. Any of theprocedures conventional in oxidizing with these oxidizing agents can beutilized to convert the alcohol of formula XVIII to the aldehyde of theformula XIX.

The compound of formula XIX is converted to the compound of the formulaXX by a Grignard reaction with the compound of formula XIII. Thisreaction is carried out in the same manner as described in connectionwith the conversion of isovaleraldehyde to the compound of the formulaVII. The compound of the formula XX as a 1:1 mixture of twodiastereomers can be separated into XXI-A and XXI-B by chromatography.Any conventional method of chromatography can be utilized to achievethis separation. Among the preferred methods of separation is columnchromatography or high pressure liquid chromatography. In carrying outthis separation, it is generally preferred to esterify the hydroxy groupin the compound of formula XX with a lower alkanoic or aroic acid. Thisesterification provides a clean and efficient method of separating theisomers, i.e., the compound of formulae XX-A and XX-B by chromatography.Among the preferred alkanoic or aroic acids are the phenyl orsubstituted phenyl carboxylic acids. Among the preferred substitutedphenyl carboxylic acids are those where the phenyl group is substitutedin one or more positions with a nitro, amino, lower alkyl or halosubstituent. Among the preferred acids are the 3,5-dinitro benzoicacids, benzoic acid, etc. Where the compounds of the formulae XX-A andXX-B are esterified, they can be converted to the compound of formulaXXI-A and XXI-B by conventional ester hydrolysis.

The compound of the formula XXI-A is converted to the compound of theformula XXIII-A via hydrogenation with a deactivated metal hydrogenationcatalyst in the same manner as described in connection with theconversion of the compound of the formula VII-A to a compound of theformula IX-A. On the other hand, the compound of the formula XXI-B isconverted to the compound of the formula XXIII-B by chemical reductionin the same manner as described in connection with the conversion of thecompound of the formula VII-B to a compound of the formula IX-B.

The compound of the formula XXIII-A and the compound of the formulaXXIII-B can be separately converted to the compound of the formula V-Bby a Claisen reaction. In accordance with this invention, Claisenrearrangement preformed either on the compound of the formula XXIII-A orXXIII-B forms the specific diastereomer of the formula V-B which can beconverted to optically active vitamin E. This Claisen rearrangementtakes place in the same manner as described in connection with theconversion with a compound of the formula IX-A and IX-B to a compound ofthe formula V-A. In this reaction, the compound of the formula XXIII-Aand XXIII-B are separately reacted with either a compound of the formulaXV-A, XV-B, XV-C, XV-D or XV-E with the formation of intermediates ofthe formula XXV-A or XXV-B. Where the compound of the formula XXIII-A isutilized, an intermediate of the formula XXV-A is formed and where thecompound of the formula XXIII-B is used, an intermediate of the formulaXXV-B is formed. Where the agent utilized to effect the Claisenrearrangement is a compound of the formula XV-E, the starting materialis either a compound of the formula XXIV-A or XXIV-B which is convertedto its enolated form, i.e., the compounds of the formula XXIV-A₁ andXXVIV-B₁ respectively. The formation of the compound of the formulaXXIV-A and XXIV-B and their conversion to their enolated form, i.e, thecompound of formula XXIV-A₁ or the compound of the formula XXIV-B₁ iscarried out in the manner described above.

The compound of the formula V-B where R₆ is hydrogen or alkoxy can beconverted to the compound of the formula III by reduction with a lithiumhydride reducing agent and hydrogenation. The reduction andhydrogenation can be carried out in any desired sequence. The reductionwill reduce the aldehyde or ester of formula V-B to the correspondingalcohol and the hydrogenation will reduce both double bonds formed by Aand B and the double bond at the 4,5 position. If hydrogenation iscarried out first, a compound of the formula: ##STR30##

wherein r'" is hydrogen or lower alkoxy. is formed. This hydrogenationcan be carried out where R'" is hydrogen or alkoxy in the same manner asdescribed in connection with the conversion of a compound of the formulaV-A to a compound of the formula XVII. The compound of the formula XXIXis converted to a compound of the formula III by reduction with analkali metal aluminum hydride reducing agent in the manner describedhereinbefore in connection with the reduction of a compound of theformula XVI-A to a compound of the formula XVIII. On the other hand, ifreduction of the compound of formula V-B where R₆ is hydrogen or loweralkoxy is carried out first, a compound of the formula: ##STR31##

wherein A and B are as above;

is formed. The compound of formula XXX is then hydrogenated to thecompound of formula III. Both the hydrogenation and the reduction arecarried out in the manner described hereinbefore.

Where R₆ is the compound of formula V-B forms a silyl ester or amide,this compound can be hydrolyzed by conventional methods to form thecompound of the formula: ##STR32##

wherein A and B are hydrogen. Any conventional method of amide or silylester hydrolysis such as those described hereinbefore can be utilized tocarry out this conversion. This compound can be directly converted tothe compound of formula XXVIII by hydrogenation in the manner describedin connection with the hydrogenation of a compound of the formula V-A.

The compound of the formula V-B where R₆ is an amide or silyl esterfunctional group can be converted to the compound of formula XXVII byhydrogenation in the manner described hereinbefore in connection withthe hydrogenation of the compound of the formula V-A. The compound offormula XXVII can be converted to the compound of the formula XXVIII byhydrolysis. Any conventional method of amide or silyl ester hydrolysisdescribed hereinbefore can be utilized in this conversion. The compoundof the formula XXVIII is esterified by conventional means with a loweralkanol or reactive derivative thereof to form the lower alkyl ester ofthe compound of formula XXVIII. On the other hand, where R₆ in thecompound of formula V-B is an ester, reduction of the compound offormula V-B will give the ester of the compound of formula XXIX. Thisester can be converted to the compound of the formula III by reductionwith an alkali metal hydride reducing agent. This reduction can becarried out in the manner described in connection with the conversion ofa compound of the formula XVI-A to a compound of the formula XVIII.

The intermediates of this invention are also due to their fragrance asuseful as oderants or as additives to oderant compositions. Forinstance, the compound of formula V-A wherein R₆ is lower alkoxy, acompound of the formula: ##STR33##

wherein R₆ " is lower alkoxy;

has a fruity, woody, musty odor. On the other hand, a compound of theformula IX-B has an odor characterized as of olives, pimento, pepper andpaprica. The compounds of formula XXV and IX-B are distinguished bytheir particular odor properties. On this basis, they can be used forperfumery purposes such as manufacture of perfumes of for perfumingproducts of all kinds such as cosmetic articles (soaps, powders, creams,lotions, etc.) The content of compounds of formula V in odorantcompositions is governed by the intended use and can vary within widelimits, for example, between 0.005-30 wt. percent.

As stated hereinabove, the novel odorant compositions produced inaccordance with the present invention which have excellent odorproperties, may be utilized in a wide range of odor compositionscontaining them. Preferable, however, they are utilized in amountsranging from about 0.5 to about 20% by weight in the compositionscomprising them. And, for example, when utilized for the perfumingsoaps, between 1 and 2% by weight of such perfume compositions willsuffice. In compositions such as lotions, suitably hand lotions and thelike, from between 2 to about 3% by weight of such compositions areutilized and in bath salts and essences, depending on the type ofcomposition, between 0.3 and 5% by weight of the composition areutilized.

The following examples are illustrative but not limitative of theinvention. All temperatures are in degrees centrigrade and the ether isdiethyl ether. The term 5% pd-C designates a carbon catalyst containing5% by weight palladium and 95% by weight carbon. The term THF designatestetrahydrofuran and the term HMDA describes hexamethylenephosphoramide.The term concentrated aqueous hydrochloric acid designates 10 Nhydrochloric acid. The term Kugelrohr designates evaporationdistillation. The term Lindlar catalyst designates a catalyst preparedfrom palladium calcium carbonate and lead acetate as described inOrganic Synthesis Collective Volume 5; pages 880-883 (1973).

EXAMPLE 1 Preparation of 6-methyl-2-heptyn-4(R,S)-ol

To a 5 l. three-necked round bottom flask equipped with a mechanicalstirrer, dropping funnel and reflux condenser was added 78.5 g. (3.23mol) of magnesium (the system was flushed with Argon) into 2 l. of dryether. Over a period of 21/2 hour was added dropwise 338 g. (3.13 mol)of ethyl bromide (freshly distilled). When the addition was completed,the reaction mixture was refluxed for one hour. The dropping funnel wasreplaced with a gas inlet tube and into the refluxing ethyl magnesiumbromide solution was bubbled 143 g. (3.6 mol) of dried methyl acetylene,which was recycled six times over a period of four hours. At the end ofthe reaction a greenish viscous oil appeared.

The flask was cooled to 0° C. in an ice-salt bath with rapid stirringand under an Argon flow 221 g. (2.58 mol) of distilled isovaleraldehydewas added dropwise over a period of one hour at such a rate that theinside reaction temperature did not exceed 5° C. After the addition wascomplete, it was allowed to stir for thirty minutes. The reactionmixture was worked up by slowly pouring it into a solution of NH₄ Cl(400 g.) in 2 l. of water with stirring. It was transferred to aseparatory funnel and extracted four times with ether. The combinedether extracts were washed three times with water and dried over MgSO₄and concentrated in vacuo. The crude light yellow oil was distilled at60° /3 mmHg to yield 264 g. (81.5%) of 6-methyl-2-heptyn-4(R,S)-ol as acolorless oil.

EXAMPLE 2 Preparation (R,S)-6-methyl-2-heptyn-4-ol-hydrogenphthalate

To a 2 l. round bottom flask was added 220 g. (1.74 mol) of6-methyl-2-heptyn-4(R,S)-ol, 265 g. (1.76 mol) of phthalic anhydride,and 220 ml. of dry pyridine. The mixture was refluxed for four hours ona steam bath. After cooling to room temperature, the content wastransferred into a separatory funnel with 500 ml. of ether. The ethersolution was washed with 1 N HCl (3 × 500 ml.) and extracted with 1 NNH₄ OH (3 × 500 ml.). The combined NH₄ OH extract was washed again withether (2 × 500 ml.) and cooled to 0° C. It was acidified to Congo redwith concentrated hydrochloric acid and extracted with CHCl₃ (3 × 500ml.) The combined chloroform extract was washed with water and dried(MgSO₄). Evaporation of solvent to dryness at reduced pressure affordeda light brown colored residue, which was crystallized in ethanol waterto give 428 g. (89.5% yield) of (R,S)=6-methyl-2-heptyn-4-olhydrogenphthalate as white crystals, m.p. 103° -105° .

EXAMPLE 3 S- (-)-6-methyl-2-heptyn-4-ol hydrogen phthalate

To a solution of 202 g. (0.736 mol) of R,S-acid,(R,S)-6-methyl-2-heptyn-4-ol hydrogen phthalate in ether (3.01.) wasadded 122 g. (1.092 mol) of S- (-)-α-methylbenzylamine. The mixture wasstirred at 25° under N₂ for 2.0 hours. The crystalline material wasfiltered off and washed again with 500 ml. of ether. It wasrecrystallized from methanol-ether to a constant rotation. The yield was102.70 g of S-α -methylbenzylamine salt of S-(-)-6-methyl-2-heptyn-4-olhydrogen-phthalate as very fine needles = m.p. 125° -136° , [α]_(D) ²⁵ -27.39° (c 1.05, CHCl₃).

A suspension of 102.70 g. (0.260 mol) of this salt in 100 ml. of etherand 500 ml. of 1 N HCl was stirred at 25° for one hour. It was washedinto a separatory funnel with ether and the layers separated. The etherphase was washed with 1 N HCl and the combined aqueous phase was againextracted with ether. The combined ether extract was washed with waterand dried (MgSO₄). Evaporation of ether to dryness at reduced pressuregave a light yellow oil, which was crystallized from ethanol-water togive 70.4 g. of S-(-)-6-methyl-2-heptyn-4-ol hydrogen phthalate as whitepowdered crystals, m.p. 103°-106°, [α]_(D) ²⁵ -8.48° (c=0.990, ethanol).

EXAMPLE 4 R-(+)-6-methyl-2-heptyn-4-ol hydrogen phthalate

The mother liquor from the preparation of S-α-methylbenzylamine salt ofS-(-)-6-methyl-2-heptyn-4-ol hydrogen phthalate was treated with 1N HClto give a yellow oil. Treatment of this material with 88 g. ofR-(+)-α-methylbenzylamine as described in Example 3 gave 88.15 g. ofR-α-methylbenzylamine salt of R-(+)-6-methyl-2-heptyn-4-ol-hydrogenphthalate as very fine needles = m.p. 128° -138° C., [α]_(D) ²⁵ +27.06°(c=1.0, CHCl₃).

For the preparation of R-(+)-6-methyl-2-heptyn-4-ol hydrogenphthalate,88.15 g. of R-α-methylbenzylamine salt of R-(+)-6-methyl-2-heptyn-4-olhydrogen phthalate was treated with 1N HCl as described in Example 3 togive after crystallization from ethanol-water 61.05 g. (30.2% yield from(R,S)-6-methyl-2-heptyn-4-ol hydrogen phthalate) ofR-(+)-6-methyl-2-heptyn-4-ol hydrogen phthalate as white powderycrystals, m.p. 105° -109°, [α]_(D) ²⁵ =+7.81°, (c=0.986, ethanol).

EXAMPLE 5 (+)-6-methyl-2-heptyn-4(R)-ol

R-(+)-6-methyl-2-heptyn-4-ol hydrogen phthalate (119 g., 0.435 mol) in500 ml. of 2N NaOH was refluxed with stirring for one hour. The reactionmixture was cooled to room temperature. It was then worked up by firstextracting with chloroform (4 × 150 ml.). The combined chloroformextracts were washed with 1N HCl and water and dried (MgSO₄).Evaporation of solvent to dryness at reduced pressure gave a yellow oil,which upon distillation at 58° -59°/1.0 mmHg. afforded 44.65 g. (81.5%)of (+)-6-methyl-2-heptyn-4-(R)-ol as a colorless oil, [α ]_(D) ²⁵ +13.48 (CHCl₃).

EXAMPLE 6 (-)-6-methyl-2-heptyn-4(S)-ol

S-(-)-6-methyl-2-heptyn-4-ol hydrogen phthalate (120 g.; 0.438 mol) in500 ml. of 2N NaOH was refluxed with stirring for one hour. The reactionmixture was cooled to room temperature and worked up as in Example 5 togive a yellow oil, which was distilled to yield 47.12 g (86%) of(-)-6-methyl-2-heptyn-4-(S)-ol as a colorless oil, b.p. 54° -55°/0.3mmHg [α ]_(D) ²⁵ -13.02° (CHCl₃).

EXAMPLE 7 6-methyl-2-(cis)-hepten-4(R)-ol

25 g. (0.195 mol) of 6-methyl-2-heptyn-4(R)-ol was dissolved in n-hexane(300 ml.) and hydrogenated at 23° C. and 1atmospheric pressure in thepresence of 2.5 g. of palladium on calcium carbonate poisoned with leadoxide (Lindlar catalyst) and 1 ml. of quinoline. Over a period of 31/2hours, 5.05 l. of hydrogen was absorbed. The catalyst was filtered offand washed with n-hexane. The solvent was evaporated to dryness atreduced pressure to give a colorless oil, which upon distillation at 48°-49°/1 mmHg. yielded 23.3 g. (91.7% yield) of6-methyl-2(cis)-hepten-4(R)-ol [α]_(D) ²⁵ + 21.02° (c= 5.053, CHCl₃).

EXAMPLE 8 6-methyl-2(trans)-hepten-4(S)-ol

Into a 1 l., 3-necked round bottom flask was collected 300 ml. of dryammonia at -78°. To this was added 11.3 g. (0.492 mol) of sodium metalin small pieces while the flask was cooled in a dry ice-acetone bath. 20g. (0.159 mol) of 6-methyl-2-heptyn-4(S)-ol in 25 ml. of dry ether wasthen slowly added to the above blue solution with stirring. Afteraddition was complete, the dry ice-acetone bath was removed, and a dryice-acetone condenser was placed in the flask. It was refluxed for 6.0hour (dark blue color did not fade). Ammonium chloride (2.0 g.) wasslowly added until the blue color disappeared, then 50 ml. of saturatedammonium chloride solution was carefully added again. Ammonia wasallowed to evaporate slowly. The solution was extracted three times withether. The combined ether extracts were washed with three times, eachwith 1 N HCl and water, dried over MgSO₄ and concentrated in vacuo.Distillation of the crude yellow oil yielded 16.36 g. (80.5%) of6-methyl-2(trans)-hepten-4(S)-ol as a colorless oil, b.p. 43° -44°/0.6mmHg.

EXAMPLE 9 3(S),7-dimethyl-4(trans)-octenoic acid ethyl ester

From 6-methyl-2(cis)-hepten-4(R)-ol

To a 100 ml. three-necked round bottom flask equipped with distillinghead and kept under Argon was added 5.0 g. (3.9 × 10⁻ ² mol) of6-methyl-2(cis)-hepten-4(R)-ol, 290 mg. (3.92 × 10⁻ ³ mol) of propionicacid and 44.5 g. (0.274 mol) of triethyl orthoacetate. The solution washeated slowly to reflux and ethanol was distilled off. The distillinghead was replaced with a reflux condenser and the solution was refluxedfor 3 hours at 142° C. The excess of triethyl orthoacetate was distilledoff at reduced pressure and the crude product was vacuum distilled togive 3.96 g. (51% yield) of 3(S),7-dimethyl-4(trans)-octenoic acid ethylester as a colorless oil, b.p. 66°-67°/0.9 mmHg., [α]_(D) ²⁵ + 19.05(c=4.882, CHCl₃).

EXAMPLE 10 3(S),7-dimethyl-4(trans)-octenoic acid

The ester, 3(S),7-dimethyl-4(trans)-octenoic acid ethyl ester (1.50 g.7.56 × 10⁻ ³ mol) was refluxed in 3 ml. of 6N NaOH, 5 ml. of methanolfor 2 hours. It was diluted with water (200 ml.) and extracted withdiethyl ether (2 × 50 ml.). The aqueous phase was cooled in an ice-bathand acidified with concentrated hydrochloric acid to Congo red. It wasthen extracted with diethyl ether (3 × 50 ml.). The combined etherextracts were washed with water (2 × 50 ml.) and dried (MgSO₄).Evaporation of ether to dryness in a rotary evaporator gave 0.98 g. (76%yield) of 3(S),7-dimethyl-4(trans)-octenoic acid, b.p. 52°-53°/0.20mmHg, [α]_(D) ²⁵ + 27.53 (c=5.071, CHCl₃).

EXAMPLE 11 3(R),7-dimethyl octanoic acid ethyl ester

Hydrogenation: 3(S),7-dimethyl-4(trans)-octenoic acid ethyl ester (1.15g.) was hydrogenated at 23°, atmospheric pressure in the presence of 5%Pd/C (500 mg.) in ethanol (20 ml.) for 4 hours to give 893 mg. (77%yield) of 3(R),7-dimethyl octanoic acid ethyl ester, [α]_(D) ²⁵ + 3.59°(c=5.268, CHCl₃).

EXAMPLE 12 3(R),7-dimethyl-octanoic acid

Hydrolysis: 400 mg. (2 mmol) of 3(R),7-dimethyl octanoic acid ethylester was refluxed in 6N NaOH (1 ml.) and methanol (4 ml.) for 2 hours.It was worked up as in Example 10 to give 207 mg. (60% yield) of3(R),7-dimethyl octanoic acid (R-(+)-dihydrocitronellic acid), [α]_(D)²⁵ + 6.81° (c=5.039, CHCl₃).

EXAMPLE 13

By the procedure of Example 9, 5.0 g. (3.91 × 10⁻ ² mol) of6-methyl-(2-trans)-hepten-4(S)-ol, 290 mg. (3.92 × 10⁻ ³ mol.) ofpropionic acid and 44.5 g. of triethylorthoacetate were reacted toproduce 3.53 g. (45%) of 3(S),7-dimethyl-4(trans)-octenoic acid ethylester as a colorless oil, b.p. 33°-35°/0.2 mmHg., [α]_(D) ²⁵ + 18.42° (c5.033, CHCl₃).

The ester (1.01 g.) was refluxed in 2N NaOH (2ml.) and methanol (10 ml.)for 2 hours. It was worked up as in Example 10 to give 416 mg. (48%yield) of 3(S),7-dimethyl-4(trans)-octenoic acid, b.p. 52°-55°/0.30mmHg. [α]_(D) ²⁵ + 27.65° (c=5.093, CHCl₃).

EXAMPLE 14 Preparation of 3(R),7-dimethyl octanoic acid ethyl ester

By the procedure of Example 11, 2.43 g. of3(S),7-dimethyl-4(trans)-octenoic acid ethyl ester obtained from example13 was hydrogenated at 23°, atmospheric pressure in the presence of 5%Pd/C in ethanol for 2 hours. Kugelrohr distillation at 39°-45°/0.2 mmHggave 1.796 g. of 3(R),7-dimethyl octanoic acid ethyl ester, [α]_(D) ²⁵ +3.29° (c = 4.65, CHCl₃).

EXAMPLE 15 Preparation of 3(R),7-dimethyloctanoic acid(R-(+)-dihydrocitronellic acid)

300 mg. of 3(R),7-dimethyl octanoic acid ethyl ester obtained fromexample 14 was refluxed in 6N NaOH (1 ml.), methanol (4 ml.) for 2hours. It was worked up as in Example 10 to give 226 mg. (87.5% yield)of R-(+)-dihydrocitronellic acid, b.p. 54°/0.4 mmHg. (Kugelrohr),[α]_(D) ²⁵ + 6.31° (c=5.069, CHCl₃).

EXAMPLE 16 3(S),7-dimethyl-4(trans)-octenoic acid dimethylamide

From 6-methyl-2(cis)-hepten-4(R)-ol

To a 50 ml. round bottom flask was added 2.0 g. (1.56 × 10⁻ ² mol) of6-methyl-2(cis)-hepten-4(R)-ol, 4 g. of1-dimethylamino-1,1-dimethoxyethane and 20 ml. of xylene. It wasrefluxed for 17 hours. The xylene was stripped off and the crude productwas purified by distillation to give 2.54 g. (82.5% yield) of a paleyellow oil, b.p. 115°-116°/1.5 mmHg. [α] _(D) ²⁵ + 19.36° (c=5.087,CHCl₃).

EXAMPLE 17 Preparation of 3(R),7-dimethyl octanoic acid dimethylamide

2.0 g. of 3(S),7-dimethyl-4(trans)-octenoic acid dimethylamide in 20 ml.of methanol was hydrogenated at 22°, atmospheric pressure in thepresence of 5% Pd/C (100 mg.) to give 1.89 g. of 3(R), ),7-dimethyloctanoic aid dimethylamide, b.p. 60°/0.4 mmHg (Kugelrohr), [α] _(D) ²⁵ +1.18° (c=5.101, CHCl₃).

EXAMPLE 18 Preparation of 3(R),7-dimethyloctanoic acid orR-(+)-dihydrocitronellic acid

3(R),7-dimethyl octanoic acid dimethylamide (600 mg.) in 4 ml. ofconcentrated HCl was refluxed with stirring for 48 hours at 100°-110°.The hydrochloric acid was removed at reduced pressure. The light redbrown residue was transferred to a separatory funnel with water, thenwith ether. The aqueous layer was extracted three times wih ether. Thecombined ether extracts were washed with water and dried (MgSO₄) andconcentrated in vacuo. The crude product was urified by Kugelrohrdistillation at 66°/0.5 mmHg to give 431 mg. (83%) of3(R),7-dimethyloctenoic acid or R-(+)-dihydrocitronellic acid, [α] _(D)²⁵ + 6.90° (c =5.03, CHCl₃).

EXAMPLE 19

By the procedure of Example 16, 2.0 g. of6-methyl-2(trans)-hepten-4(S)-ol and 4 g. of1-dimethylamino-1,1-dimethoxy ethane were reacted in 20 ml. of xylene byrefluxing for 17 hours. It was worked up as described in Example 16 togive 2.91 g. (94.5%) of 3(S),7-dimethyl-4(trans)-octenoic aciddimethylamide as a pale yellow oil, b.p. 103°-104°/0.7 mmHg. [α] _(D)²⁵ + 20.64° (c=5.033, CHCl₃).

EXAMPLE 20

By the procedure of Example 17,2.0g. of3(S),7-dimethyl-4(trans)-octenoic acid dimethylamide was hydrogenated inmethanol (20 ml.) with the presence of 5% Pd-C (100 mg.) at 22°, 1atmosphere to give 1.78 g. of 3(R),7-dimethyl octanoic acid dimethylaideas a pale yellow oil, b.p. 60°/4 mmHg (Kugelrohr).

EXAMPLE 21 Preparation of 3(R),7-dimethyloctanoic acid(R-(+)-dihydrocitronellic acid)

The 3(R),7-dimethyl octanoic acid dimethylamide (850 mg.) was hydrolyzedin 5 ml. of concentrated aqueous HCl for 48 hours. It was worked up asin Example 18 to give 579 mg. (78.8%) of 3(R),7-dimethyloctanoic acid orR-(+)-dihydrocitronellic acid, b.p. 64°/0.4 mmHg (Kugelrohr), [α] _(D)²⁵ + 6.82° (c=5.1013, CHCl₃).

EXAMPLE 22 6-methyl-2(cis)-hepten-4(R)-ol acetate

4.0 g. of 6-methyl-2(cis)-hepten-4(R)-ol in 6 ml. of acetic anhydrideand 6 ml. of dry pyridine was allowed to stand at 23° C. for 17 hours.It was diluted with water and extracted three times with ether. Thecombined ether extracts were washed three times each with lN HCl, waterand dried (MgSO₄). After removal of solvent in vacuo the crude productwas distilled to give 4.868 g. (91.8% yield) of6-methyl-2(cis)-hepten-4(R)-ol acetate as a colorless oil, b.p. 39°/0.5mmHg. [α] _(D) ²⁵ - 14.21° (c = 4.886, CHCl₃).

EXAMPLE 23 6-methyl-2(trans)-hepten-4(S)-ol acetate

5.0 g. of 6-methyl-2(trans)-hepten-4(S)-ol, 7.5 ml. of acetic anhydrideand 7.5 ml. of anhydrous pyridine were allowed to stand at roomtemperature for 17 hours. It was worked up as in Example 22 to give6.492 g. (97.5% yield) of 6-methyl-2(trans)-hepten-4(S)-ol acetate as acolorless oil, [α] _(D) ²⁵ - 57.45° (c 5.0185, CHCl₃).

EXAMPLE 24 3(S)7-dimethyl-4(trans)-octenoic acid from6-methyl-2(cis)-hepten-4(R)-ol acetate

To a dry 100 ml. three-necked round bottom flask equipped with droppingfunnel, septum and magnetic stirrer was added 4.67 ml. (10.3 mmol) ofn-butyl lithium (2.2 M in n-hexane) under Argon. The flask was cooled inan ice-bath and 1.78 ml. (10.5 mmol) of N-isopropylcyclohexylamine(distilled from calcium hydride) in 2.0 ml. of anhydrous THF was addeddropwise. The hexane was first removed at reduced pressure underanhydrous conditions and the flask was then cooled to -78° C. It wasthen charged with 3 ml. of HMPA (distilled from calcium hydride). Thiswas followed by the slow dropwise addition of 1.702 g. (10.0 mmol) of6-methyl-2(cis)-hepten-4(R)-ol acetate in 2 ml. of anhydrous THF. Thereaction mixture was stirred for 10 minutes after addition was completeto the resulting clear yellow slurry which was formed with the lithiumenolate of 6-methyl-2(cis)-hepten-4(R)-ol. To this enolate, there wasthen added 1.65 g. (11.0 mmol) of t-butyldimethylchlorosilane in 2 ml.of THF. The reaction mixture was stirred at -78° C. for ten minutes toallow the formation of the intermediateR[6-methyl-2(cis)-hepten-4-yl]-O-dimethyl-tertbutyl silyl ketene] andthen at room temperature over a period of 2 hours. The clear lightyellow solution was taken up in 300 ml. of pentane and washed with water(3 × 50 ml.), once with brine and dried (MgSO₄). The solvent was removedin a rotary evaporator and the crude product was distilled at40°-50°/0.5 mmHg. to give 2.77 g. of 3(S),7-dimethyl-4(trans)-octenoicacid t-butyldimethylsilyl ester as a yellow oil.

The above silyl ester was hydrolyzed in 10% HCl (5 ml.) and THF (25 ml.)at room temperature for 17 hours. The solution was poured into 30 ml. of5% NaOH and extracted wih ether. The alkaline aqueous phase was cooledto 0° C. and acidified to Congo red with concentrated hydrochloric acid.The aqueous phase was extracted three times with ether. The etherextracts were combined, washed successively with water, saturated brineand dried (MgSO₄). Evaporation of ether and distillation of the crudematerial at 55°/0.4 mmHg. (Kugelrohr) yielded 1.06 g. (62%) of3(S),7-dimethyl-4(trans)-octenoic acid as a colorless oil, [α]_(D) ²⁵ +27.21° (c = 4.745, CHCl₃).

EXAMPLE 25 Preparation of 3(R),7-dimethyl-octanoic Acid

500 mg. of 3(S), 7-dimethyl-4(trans)-octanoic acid obtained from example24 in ethyl acetate (20 ml.) was hydrogenated at 23° C. and atmosphericpressure in the presence of 5% Pd/C (50 mg.) for 1/2 hour until 70.3 mlof hydrogen was taken up. The catalyst was filtered off and washed wihethyl acetate (20 ml.). The combined filtrate was evaporated at reducedpressure to give an oil, which upon Kugelrohr distillation at 54°/0.4mmHg gave 398 mg of pure R-(+)-dihydrocitronellic acid as a colorlessoil, [α]_(D) ²⁵ + 5.93° (C4.652,CHCl₃).

EXAMPLE 26 3(S),7-dimethyl-4(trans)-octenoic acid from6-methyl-2(trans)-hepten-4(S)-ol acetate

This Example was carried out exactly the same as described in Example24. The amount of reagents used were as follows: N-isopropylcyclohexylamine (1.78 ml., 10.5 mmol), n-butyllithium (4.67 ml.), HMPA(3 ml.), t-butyldimethylchlorosilane (1.65 g.) and 1.702 g. (10.0 mmol)of 6-methyl-2(trans)-hepten-4(S)-ol acetate. It was worked up as inExample 24 to give 2.85 g. of yellow oil containing mainly thet-butyldimethylsilylester of 3(S),7-dimethyl-4(trans)-octenoic acid.This material was treated with 10% HCL(5 ml.) in THF (25 ml.) at roomtemperature for 45 minutes. The solution was poured into 30 ml. of 5%aqueous NaOH and extracted with ether. The aqueous phase was cooled to0° C. and acidified to Congo red wih concentrated hydrochloric acid. Itwas then extracted with ether. The combined ether extracts were washedwith water, saturated brine and dried. Evaporation of ether to drynessand distillation of the crude material at 57°/0.4 mmHg. (Kugelrohr) gave873 mg. (51.2% yield) of 3(S),7-dimethyl-4(trans)-octenoic acid, [α]_(D)²⁵ + 24.09° (c = 3.35, CHCl₃).

EXAMPLE 27 Preparation of 3(R),7-dimethyl octanoic acid orR-(+)-dihydrocitronellic acid

500 mg. of 3(S),7-dimethyl-4(trans)-octenoic acid from example 26 washydrogenated in ethyl acetate (20 ml.), 50 mg. of 5% Pd/C at 23° .atmospheric pressure to give 488 mg. (96.5% yield) ofR-(+)-dihydrocitronellic acid after distillation (Kugelrohr) a 56°/0.4mmHg., [α]_(D) ²⁵ + 6.14° (c = 5.025, CHCl₃ ).

EXAMPLE 28 3(S),7-dimethyl-4(trans)-octenal from6-methyl-2-(cis)-hepten-4(R)-ol

6-methyl-2(cis)-hepten-4(R)-ol (1.5 g., 11.7 mmol), 15 ml. of ethylvinyl ether and 3.5 g. (11.0 mmol) of mercuric acetate were refluxed(45° C under Argon for 21 hours. More ethyl vinyl ether (5 ml.) and 40ml. of benzene were added and refluxing was continued for 4hours. Thesolution was cooled to room temperature and 1 ml. of glacial acetic acidwas added. The reaction mixture was stirred at room temperature for onehour and then diluted with 150 ml. of ether. The solution was washedfour times with 5% by weight aqueous KOH and dried over anhydrous K₂CO₃. The ether was evaporated to dryness at reduced pressure and thecrude product was distilled (Kugelrohr) at 30°-60°/40 mmHg to give 1.578g. of colorless liquid which was the vinyl ether of6-methyl-2(cis)-hepten- 4(R)-ol.

The above vinyl ether was dissolved in benzene (100 ml.) and thesolution was refluxed for 120 hours under Argon. The solvent was removedat reduced pressure to give a yellow oil (˜1.289 g.). This waschromatographed on 25 g. of silica gel and elution with 1:9 parts byvolume of ether:petroleum ether (b.p. 30°-60°) gave 792 mg. of material.This was further purified by Kugelrohr distillation at 36°/0.5 mmHg toyield 3(S), 7-dimethyl-4(trans)- octenal as a colorless oil, [α] _(D)25 + 30.18° (c =3.572, CHCl₃).

Example 29 Conversion of 3(S),7-dimethyl-4(trans)-octenal to R-(+)-dihydrocitronellic acid

To a 50 ml. round bottom flask was added 500 mg. (3.25 mole) of3(S),7-dimethyl-4-(trans)-octenal in 10 ml. of ethanol and 1.10 g. (6.50mmol) of silver nitrate in 20 ml. of water. To this was added dropwise2.17 ml. (13.0 mmol) of 6 N aqueous NaOH. A black precipitate appearedand it was stirred at 23° for one 1/2 hours. The precipitate wasfiltered and washed with 15 ml. each of 0.1 N NaOh, H₂ and ether. Theaqueous layer was separated and extracted twice with ether. It was thencooled to 0° C. and acidified to Congo red with concentratedhydrochloric acid. It was extracted with ether and the combined etherextracts were washed with water and dried (MgSO₄) and concentrated invacuo. The crude slightly yellow material was distilled (Kugelrohr) at56° /0.5 mmHg to give 375 mg. (68% yield) of 3(S),7-dimethyl-4(trans)-octenoic acid, [α ] _(D) 25 + 27.20 (c = 5.1835, CHCl.sub. 3).

260 mg. of 3(S),7-dimethyl-4-(trans)-octenoic acid was hydrogenated bythe procedure of Example 25 at 23° , atmospheric pressure (inethylacetate 10ml) and in the presence of 5% Pd.C(25mg)for one hr. Itwas worked up as in Example 25 to give after distillation (Kugelrohr 56°/0.5 mmHg.) 227 mg. (86% yield) of 3 (R), 7 -dimethyloctanoic acid(R)-(+)-dihydrocitronellic acid), [α ]_(D) 25 + 6.23° (c= 5.138 CHCl.sub. 3).

EXAMPLE 30

3(S),7-dimethyl-4(trans)-octenal was prepared by the procedure ofExample 28 from 2.0 g. (15.6 mmol) of 6-methyl-2(trans)-hepten-4(S)-ol,20 ml. of ethyl vinyl ether and 4.6 g. (14.4 mmol) of mercuric acetateunder reflux for 21 hours. After this period, 40 ml. of benzene and 5ml. of ethyl vinyl ether were added again and further refluxed for 4hours. The reaction mixture was worked up as described in Example 28 andthe crude material was distilled (Kugelrohr) at 35° -70° /35 mmHg togive 2.938 g. of yellow oil, which on thin layer chromatography revealedthe presence of vinyl ether of 6-methyl-2(trans)-hepten- 4(S)-ol and3(S),7-dimethyl-4(trans)-octenal. This mixture of products was dissolvedin 100 ml. of benzene and the solution was refluxed under Argon for 74hours. The benzene was evaporated off at reduced pressure to give 2.52g.of crude product, which was purified by chromatography on 40g. of silicagel. Elution with 10% by volume ether in 90% volume petroleum ether(b.p. = 30°-60° ) gave 1.448 g. of 3(S),7-dimethyl-4(trans)-octenal.

EXAMPLE 31

500 mg. of 3(S),7-dimethyl-4(trans)-octenal from Example 30 was treatedas in Example 29 with 1.10 g. of AgNO₃ in 2 ml. of H₂ O and 2.17 ml. of6N NaOH at room temperature for 11/2 hour with stirring. The reactionmixture was worked up as in Example 29 and upon Kugelrohr distillationat 58° /0.06 mmHg. afforded 425 mg. of 3(S),7-dimethyl-4(trans)-octenoicacid as a colorless oil (76% yield). [α]_(D) ²⁵ + 26.45° (c= 5.0145,CHCl.sub. 3).

EXAMPLE 32

335 mg. of 3(S),7-dimethyl-4(trans)-octenoic acid was hydrogenated inethyl acetate (10 ml.) at 23° , atmospheric pressure on 5% Pd/C (30 mg).The product was purified by distillation (Kugelrohr, 56° /0.5 mmHg) togive 284 mg. of R-(+)-dihydrocitronellic acid.

EXAMPLE 33 Preparation of R-(+ )-dihydrocitronellol from R-(+)-dihydrocitronellic acid

To a 25 ml. round bottom flask was added 564 mg. of R-(+)-dihydrocitronellic acid ([α ]_(D) ²⁵ + 6.77° , CHC1₃) in 2 ml. ofabsolute diethyl ether. To this solution was added 4.59 ml. of sodiumbis (2-methoxyethoxy) aluminum hydride (70% by weight in benzene) in 5ml. of diethyl ether. The solution was stirred at 25° C. for 17 hours.It was cooled in an ice-bath and 1 ml. of water was added dropwise. Then30ml. of water containing 1 ml. of concentrated aqueous H₂ SO₄ was addedagain. The organic layer was separated and the aqueous phase wasextracted with diethyl ether (2 × 50 ml.). The ether extracts werecombined and washed with water (3 × 50 ml.). dried over anhydrous MgSO₄and concentrated in vacuo. The crude material was distilled at 50° /0.06mmHG (Kugelrohr oven) to give 460 mg. (88.9%) of R-(+)-dihydrocitronellol as a colorless oil, [α ]_(D) ²⁵ + 4.10° (c= 4.003,CHCl.sub. 3).

EXAMPLE 34 Preparation of optically pure R-(+ )-dihydrocitronellal3(R),7-dimethyl-octanal]

Into a 5.1 three-necked flask equipped with mechanical stirrer,Deanstark trap and condenser was placed 280 g. of silver carbonate oncelite (freshly prepared) and 1.51. of toluene. 15.8 g. (0.10 mol) ofR-(+ )-dihydrocitronellol in 500 ml. of toluene was added and thereaction mixture was vigorously stirred and refluxed in an Argonatmosphere for 14 hours. It was cooled to room temperature and the blackprecipitate was filtered off and washed with pentane (total 1.01.).Evaporation of solvent to dryness in a rotary evaporator (45° C/10 mmHg)afforded a light yellow oil with strong citronellal like order. Thismaterial was quickly filtered through a short column of silica gel (150mg.). Elution with 5% ether in petroleum ether (b.p. 30°-60° ) gave 8.60g. of aldehyde. Further elution with ether afforded R-(+)-dihydrocitronellol. The aldehyde was further purified by Kugelrohrdistillation at 55°-60° /0.8 mmHg to give 7.26 g. of pure R-(+)-dihydrocitronellal as a colorless oil, [α ]_(D) ²⁵ + 14.07°(c= 5.074,CHCl.sub. 3).

EXAMPLE 35 Preparation of 6(R),10-dimethyl-9undecen-2-yn-4(S)-ol and6(R)10 -dimethyl-9-undecen-2-yn-4(R)-ol 150 g. (0.964mol.) of3(R),7-dimethyl-6-octen-1-al in 200 ml. of ether was added dropwise to asuspension of propynylmagnesium bromide (prepared from 133 g. of ethylbromide, 32.9 g. of magnesium and 120 g. of propyne in 900 ml. of ether)at 5% with vigorous stirring. After completion, the reaction mixture wasgradually warmed to room temperature and worked up in the manner ofExample 1 to give 182.45g. of crude product. Distillation of thismaterial gave 169.6 g. (90.8%) of 6(R),10-dimethyl-9-undecen-2-yn- 4-(R,S)-ol as a colorless oil, b.p. 95° /0.30 mmHg. 22 g. of the abovematerial was chromatographed on 2.0 kg. of silica gel. Elution with30°-40° ether in petroleum ether gave 5.29 g. of pure6(R),10-dimethyl-9-undecen-2-yn-4-(S)-ol as the fast moving spot. [α]_(D) ²⁵ - 7.83° (c=2.441, CHCl.sub. 3). Further elution gave 4.0 gramsof pure 6(R),10-dimethyl-9-undecen-2-yn-4R-ol [α ]_(D) ²⁵ + 9.07 (c=5.038, CHCl.sub. 3). EXAMPLE 36 6(R),10-dimethyl-2(trans)9-undecadien-4(S)-ol

Into a three-necked flask equipped with condenser, dropping funnel andmagneitc stirrer was placed 2.0 g. (0.0103 mol) of 6(R),10-dimethyl-9-undecen-2-yn-4(S)-ol in 120 ml. of dry ether. The system was flushedwith Argon and 3.02 ml. of sodium bis-2-methoxyethoxy) aluminum hydride(1.0 g. atom of hydrogen per 140 cc. in benzene) in 40 ml. of dry etherwas added dropwise in such manner that a gentle reflux was maintained.After complete addition of reagent it was further refluxed for 17 hours.The reaction mixture was cooled to 0° C. and 20 ml. of dilute sulfuricacid (4:1, H₂ O, H₂ SO₄) was added carefully and followed by 200 ml. ofwater and 200 ml. of ether while stirring was continued. The layers wereseparated and the aqueous phase was further extracted with ether. Thecombined ether extract was washed with 5% NaHCO₃, brine and dried overHA₂ SO₄. Evaporation of ether to dryness in vacuo affored 1.77 g. oflight yellow oil, which was purified by Kugelrohr distillation at 58°-60° /0.20 mmHg to give 1.412g. (70% yield) of6(R),10-diemthyl-2(trans)-9-undecadien-4(S)-ol as a colorless oil.

EXAMPLE 37 6(R), 10-dimethyl-2(cis)-9-undecadien-4(R)-ol

1.5 g. of 6(R), 10-dimethyl-9undecen-2-yn-4(R)-ol was dissolved in 70ml. of n-hexane containing 0.6 ml. of quinoline was hydrogenated at 24°,atmospheric pressure, in the presence of 150 mg. of Lindlar catalyst(palladium on calcium carbonate poisoned with lead oxide). It was workedup in the manner of Example 7 to give, after distillation (Kugelrohr48°-60°/0.07 mmHg., 1.485 g. of 6(R),10-dimethyl-1-2-(cis)-9-undecadien-4(R)-ol.

EXAMPLE 38 3(S), 7(R), 11-trimethyl-4(trans), 10-dodecadienoic acidethyl ester

A. From 6(R), 10-dimethyl-2(trans), 9-undecadien-4(S)-ol:

To a 100 ml. three-necked flask was added 1.3 g. (6.64 mmol) of 6(R),10-dimethyl-2(trans), 9-undecadien-4(S)-ol, 7.54 g. (46.48 mmol) oftriethyl orthoacetate and 30 mg. of propionic acid. The solution washeated to reflux slowly and ethanol was allowed to distill off. It wasfurther refluxed for 20 hours and the excess of reagent was removed in arotary evaporator. The crude material was distilled (Kugelrohr) at65°/0.20 mmHg. to give 1.26 g. (71.5% yield) of 3(S), 7(R),11-trimethyl-4(trans), 10-dodecadienoic acid ethyl ester, [α]_(D) ²⁵ +6.53 (c= 09195, n-octane).

B. From 6(R), 10-dimethyl-2(cis), 9undecadien-4(R)-ol: 0.896 g. (4.57mmol) of 6(R), 10-dimethyl-2(cis), 9-undecadien-4-(R)-ol, 5.2 g. (32mmol) of triethylorthoacetate and 4 mg. of propionic acid were heatedunder reflux for 11/2 hours after all ethanol formed had been distilledoff. It was worked up as in part A of this Example and the crude product(1.022 g.) was purified by chromatography on 50 g. of silica gel. Theproduct was 3(S), 7(R), 11-trimethyl-4(trans), 10-dodecadienoic acidethyl ester.

EXAMPLE 39

1.13 g. of 3(S), 7(R), 11-trimethyl-4(trans), 10-dodecadienoic acidethyl ester in ethylacetate (80 ml.) was hydrogenated at 23° C.,atmospheric pressure in the presence of 5% Pd/C (113 mg.). It was workedup as in Example 11 to give 1.05 g. of 3(R), 11-trimethyl-dodecanoicacid ethyl ester, [α]_(D).sup. 25 + 1.05° (c = 0.951, n-octane).

EXAMPLE 40 3(R), 7(R), 11-trimethyl-dodecanol-1

445 mg. of 3(R), 7(R), 11-trimethyl-dodecanoic acid ethyl ester and 500mg. of lithium aluminum hydride in 40 ml. of dry ether were refluxed for21/2 hours. After this period, the excess of lithium aluminum hydridewas destroyed by careful dropwise additions of 0.5 ml. of water. Afterthe 0.5 ml. of water was added, 300 ml. 3 N aqueous sulfuric acid wasadded to the reaction mixture. The reaction was then extracted threetimes (50 cc. per time) with diethyl ether. The ether extracts werecombined and washed three times with 20 cc. of 5% by weight aqueoussodium bicarbonate solution followed by three times with 30 cc. water.The ether extract was dried over anhydrous magnesium sulfate andevaporated to dryness to give 373 mg. of crude product. The product waspurified by chromatography on 20 g. of silica gel and elution with 10 %by volume ether in petroleum ether (b.p. = 30-60° C.) gave 301 mg. of3(R), 7(R), 11-trimethyl-dodecanol. A sample was distilled for analysis,b.p. 95° (bath)/ 0.05 mmHg, [α]_(D) ²⁵ + 2.55° (c= 4.436, n-octane).

EXAMPLE 41

0.712 g. of 3(R), 7(R), 11-trimethyl-4(trans), 10-dodecadienoic acidethyl ester was hydrogenated at 23° C., atmospheric pressure, in thepresence of 5% Pd/C (70 mg.) in ethyl acetate. It was worked up as inExample 11 to give 496 mg. of 3(R), 7(R), 11-trimethyl-dodecanoic acidethyl ester, [α]_(D) ²⁵ = 1.56° (c= 1.53, n-octane).

EXAMPLE 42

By the procedure of Example 40, 248 mg. of 3(R), 7(R),11-trimethyldodecanoic acid ethyl ester was reduced with lithiumaluminum hydride (270 mg.) in refluxing ether for 2 hours to yield 209mg. of 3(R), 7(R), 11-trimethyldodecanol, [α]_(D) ²⁵ + 2.42° (c=0.948,n-octane).

EXAMPLE 43 PREPARATION OF 6(R), 10-DIMETHYL-UNDECAN-2-YN-4(R)-OL AND6(R),-10-DIMETHYL-UNDECAN-2-YN-4(S)-OL

Propynyl magnesium bromide was prepared as described earlier from ethylbromide (77g, 0.405 mol, freshly distilled), magnesium (10.8 g 0.4455mol) and methyl acetylene (approximately 100 ml at -70°) in 400 ml ofabsolute diethyl ether. To this well stirred mixture was added dropwise26.4 g (0.169 mol) of 3(R), 7-dimethyloctanal (R-(+)-dihydrocitronellal)in 500 ml of dry ether while the reaction temperature was maintainedbetween 0°-5° C with external cooling. After 45 min. all aldehyde hadbeen added and the reaction was allowed to warm to 30° and stirred atthis temperature for 1.0 hr. Thin layer chromatography analysis of thereaction mixture at this point showed the disappearance of startingmaterial. The flask was then cooled in an ice-bath and 100 g of NH₄ Clin 600 ml of water was added slowly. The content was transferred to aseparatory funnel and the layers separated. The aqueous phase wasfurther extracted with ether (3 × 250 ml). The combined ether extractwas filtered quickly through Celite and washed with saturated brine (3 ×500 ml) and dried over MgSO₄. After filtration the solvent wasevaporated to dryness in a rotary evaporator (40°/25 mmHg) to give 33.1g (100%) of crude 6(R), 10-dimethyl-undecan-2-yn-4(R,S)-ol as a clearlight amber oil.

The crude product (33.1 g) was chromatographed on 3.36 kg of silica gel(70-230 mesh). Continued elution with a diethyl ether-petroleumether(30-60°). Mixture containing about 10 parts by volume of diethyl etherand 90 parts by volume of petroleum-ether gave 8.53 g of 6(R),10-dimethyl-undecan-2-yn-4-(S)-ol and, 8.37 g of 6(R),10-dimethyl-undecan-2-yn-4(R)-ol and 7.75 g mixture of the above twocompounds.

EXAMPLE 44 6(R), 10-DIMETHYL-UNDECAN-2-YN-4(S)-OL 3,5-DINITROBENZOATE

First a p-toluenesulfonyl chloride (7.75 g, 40.72 mmol) in 15 ml of drypyridine was added portionwise with stirring to a solution of3,5-dinitrobenzoic acid (4.33 g, 20.36 mmol) in 25 ml of pyridine. Thesolution was chilled in ice and 4.0 g (20.36 mmol) of 6(R),10-dimethyl-undecan-2-yn-4(S)-ol in pyridine (15 ml) was addedportionwise at such a rate so that the internal temperature did notexceed 6° C. The reaction mixture was stirred at 5° for 20 min. andpoured into 300 ml of ice-water. This was extracted with CHCl₃ (4 × 200ml). The CHCl₃ extract was washed with 2N HCl (3 × 200 ml), saturatedaqueous NaHCO₃ solution (2 × 200 ml), once with brine (200 ml) and driedover anhydrous magnesium sulfate. Evaporation of chloroform to drynessin a rotary evaporator at reduced pressure gave 7.96 g of (100% yield)of crystalline crude product. This was recrystallized once from methanolto give pure 6(R), 10-dimethyl-undecan-2-yn-4(S)-ol 3,5-dinitrobenzoate,m/p. 88°-90.5° C.

EXAMPLE 45 6(R), 10-DIMETHYL-UNDECAN-2-YN-4(S)-OL FROM 6(R),10-DIMETHYL-UNDECAN-2-YN-4(S)-OL 3,5-DINITROBENZOATE

6(R), 10-dimethyl-undecan-2-yn-4(S)-ol 3,5-dinitrobenzoate (5.4 g, 13.8mmole) and 54 ml of 6N aqueous NaOH in 250 ml of methanol were refluxedfor 11/2 hr. After evaporating most methanol off in a rotary evaporatorat reduced pressure, water (750 ml) was added. The aqueous phase wasextracted with diethyl ether (4 × 300 ml). The combined ether extractswere washed with water (3 × 300 ml), saturated brine (300 ml) and dried(MgSO₄). Removal of ether at reduced pressure afforded 2.58 g (95.5%yield) of oil. This was distilled (Kugelrohr) at 87°/0.175 mmHg to give2.10 g of pure 6(R), 10-dimethyl-undecan-2-yn-4(S)-ol as a colorlessoil.

EXAMPLE 46 6(R), 10-DIMETHYL-UNDECAN-2-yn-4(R)-OL 3,5-DINITROBENZOATE

This compound was prepared similar to the method described in Example 44from 4.22 g (21.6 mmol) of 6(R), 10-dimethyl-undecan-2-yn-4(R)-OL, 4.58g (21.6 mmol) of 3,5-dinitrobenzoic acid and 8.25 g (43.2 mmol) ofp-toluenesulfonyl chloride in dry pyridine (total 55 ml) at 4° C for31/2 hr. It was worked up as described in Example 44 to give afterrecrystallization once from methanol 6.73 g (84.2%) of pure 6(R),10-dimethyl-undecan-2-yn-4(R)-ol 3,5-dinitrobenzoate, m.p. 90-91°.

EXAMPLE 47 6(R), 10-DIMETHYL-UNDECAN-2-YN-4(R)-OL

6.65 g (0.0171 mol) of 6(R), 10-dimethyl-undecan-2-yn-4(R)-ol3,5-dinitrobenzoate and 35 ml of 6N aqueous NaOH in methanol (300 ml)were refluxed for 11/2 hr. It was worked up as in Example 45 to give3.30 g (98.8%) of pure 6(R), 10-dimethyl-undecan-2-yn-4(R)-ol as acolorless oil.

EXAMPLE 48 6(R), 10-DIMETHYL-2(TRANS)-UNDECEN-4(S)-OL

To a solution of 1.9 g (9.66 mmol) of 6(R),10-dimethyl-undecan-2-yn-4(S)-ol in 75 ml of dry diethyl ether was addeddropwise 3.02 ml of sodium bis(2-methoxyethoxy) aluminum hydride (70% byweight in benzene, 1 g-atom Hydrogen per 140 c.c.) in 60 ml of diethylether. The top of the condenser was fitted with an oil bubble seal andthe clear solution was refluxed for 20 hr. The flask was cooled in anice-bath and 20ml of 4:1 parts by volume H₂ O:H₂ SO₄ was added dropwise.This was followed by the addition of 200 ml of water and 200 ml of etherand the mixture was stirred for about 10 min. The aqueous phase wasseparated and further extracted with diethyl ether (3 × 100 ml.). Thecombined ether extract was washed with saturated aqueous NaHCO₃ solution(3 × 70 ml), water saturated brine and dried (MgSO₄). Evaporation ofether to dryness afforded 2.0 g of crude product, which on distillation(Kugelrohr, 85°/1.1 mmHg) gave 1.61 g (83.8% yield) of pure 6(R),10-dimethyl-2-(trans)-undecen-4(S)-ol as a colorless oil.

EXAMPLE 49 6(R), 10-DIMETHYL-2(CIS)-UNDECEN-4(R)-OL

3.2 g of 6(R), 10-dimethyl-undecan-2-yn-4(R)-ol, 320 mg of Lindlarcatalyst (Pd-CaCO₃ -PbO) and quinoline (0,6 ml) in n-hexane (120 ml)were stirred and hydrogenated at 23° C, atmospheric pressure for 1.0 hruntil 395 ml of hydrogen was taken up. The catalyst was filtered off andwashed with 100 ml of n-hexane. The hexane was washed with IN aqueous H₂SO₄ (3 × 30 ml), saturated aqueous NaHCO₃ solution (3 × 30 ml), water (3× 30 ml) and dried (MgSO₄). Evaporation of solvent to dryness at reducedpressure gave 6(R), 10-dimethyl-2(cis)-undecen-4(R)-ol as a colorlessoil. b.p. 102°/0.2 mmHg (Kugelrohr).

EXAMPLE 50 3(S), 7(R), 78 11-TRIMETHYL-4(TRANS)-DODECENOIC ACIDDIMETHYLAMIDE

850 mg of 6(R), 10-dimethyl-2(cis)-undecen-4(R)-ol and 2.0 g ofN,N-dimethylacetamide dimethyl acetal were refluxed in 20 ml of xylenefor 20 hr. The xylene was removed at 55°/ 10 mmHg and the crude productwas purified by Kugelrohr distillation at 68°-71°/0.15 mm to give 1.042g (91%) of 3(S), 7(R), 11-trimethyl-4(trans)-dodecenoic aciddimethylamide as a light yellow oil.

EXAMPLE 51 3(R), 7(R), 11-TRIMETHYL DODECANOIC ACID DIMETHYLAMIDE

850 mg of 3 .sup.(S) , 7(R), 11-trimethyl-4(trans)-dodecenoic aciddimethylamide and 90 mg of 5% by weight palladium on 95% by weightcharcoal were hydrogenated in 60 ml of ethylacetate for 5.0 hr. at 23° Cand atmospheric pressure. The catalyst was filtered off and washed withethylacetate. The solvent was evaporated to dryness at reduced pressureto give a crude product which was distilled at 68°-72°/0.15 mmHg(Kugelrohr) to give 750 mg of 3(R), 7(R), 11-trimethyl dodecanoic aciddimethylamide as a colorless oil.

EXAMPLE 52 3(S), 7(R), 11-TRIMETHYL-4-(TRANS)-DODECENOIC ACID ETHYLESTER

6(R), 10-dimethyl-2(cis)-undecen-4(R)-ol (2.9 g, 1.46 mmol) triethylorthoacetate (16.5 g) and propionic acid (57 mg) were refluxed for 2.0hr, while the ethanol formed was removed by distillation. The excess oftriethyl orthoacetate was then distilled off at about 1 mmHg to give3.904 g of residue. This was further purified by distillation(Kugelrohr) at 95°-101°/ 0.10 mmHg to give 3.598 g (91.1% yield) of3(S), 7(R), 11-trimethyl-4-(trans)-dodecenoic acid ethyl ester as acolorless oil.

EXAMPLE 53

As described in Example 52, 1.44 g of 6(R),10-dimethyl-2-(trans)-undecen-4(S)-ol, 9.05 g of triethyl orthoacetateand 34 mg of propionic acid were refluxed for 1 hr. 45 min. under thedistillation removal of ethanol. The crude product was purified bydistillation (Kugelrohr, 96°-105°/0.25 mmHg) to give 1.51 g of 3(S),7(R), 11-trimethyl-4(trans)-dodecenoic acid ethyl ester.

EXAMPLE 54 3(R), 7(R), 11-TRIMETHYL-DODECANOIC ACID ETHYL ESTER

3.53 g of 3(R), 7(R), 11-trimethyl-4(trans)-dodecenoic acid ethyl esterin ethyl acetate (120 ml) was hydrogenated in the presence of 360 mg of5% by weight palladium on 95% by weight charcoal, at 23° and atmosphericpressure for 21/2 hr. until no more hydrogen was absorbed (350 ml of H₂being taken up). The catalyst was filtered off and the filtrate wasevaporated to dryness at reduced pressure to give 3.55 g of colorlessoil. This was purified by distillation (Kugelrohr, 101°-107°/0.15 mmHg)to yield 3.44 g of pure 3(R), 7(R), 11-trimethyl-dodecanoic acid ethylester.

EXAMPLE 55 3(R), 7(R), 11-TRIMETHYL-DODECANOIC ACID

145 mg of 3(R), 7(R), 11-trimethyl-dodecanoic acid ethyl ester and 0.5ml of 6N aqueous NaOH were refluxed in 3 ml of methanol for 2.0 hr. Themethanol was removed at reduced pressure and water (100 ml) was added.The aqueous alkaline solution was extracted with diethyl ether (2 × 30ml), cooled in an ice-bath, and acidified with concentrated hydrochloricacid. The acidic aqueous solution was extracted with diethyl ether (3 ×20 ml). The combined ether extract was washed with water (3 × 20 ml) anddried (Mg SO₄). Evaporation of ether to dryness at reduced pressure gave107mg of light yellow oil, which was distilled (Kugelrohr 135-139°/0.2mm) to yield 101 mg of 3(R), 7(R), 11-trimethyl-dodecanoic acid as acolorless oil.

EXAMPLE 56 3(R), 7(R), 10-TRIMETHYL-DODECANOL-1

3.13 g (0.01157 mol) of 3(R), 7(R), 10-trimethyl-dodecanoic acid ethylester in dry ether (35 ml) was added dropwise to a mixture of lithiumaluminum hydride (3.0 g) in 150 ml of dry diethyl ether. The mixture wasrefluxed with stirring for 21/2 hr. The flask was cooled in an ice-bathand the excess of lithium aluminum hydride was destroyed by carefullyadding water, followed by 450 ml of 2N H₂ SO₄. The aqueous phase wasextracted with diethyl ether (3 × 150 ml.). The ether extract was washedwith water (3 × 50 ml), saturated aqueous NaHCO₃ (3 × 50 ml), water (3 ×50 ml), and dried over anhydrous magnesium sulfate. Evaporation of etherto dryness at reduced pressure yielded 2.70 g of crude material which ondistillation (Kugelrohr oven, 104°-110°/0.10 mmHg) afforded 2.572 g(97.5%) of 3(R), 7(R) 11-trimethyl-dodecanol as a colorless oil.

We claim:
 1. A process for preparing a compound of the formula:##STR34## wherein R₆ is hydrogen, lower alkoxy, or, ##STR35## and n isan integer of from 0 to 1; A and B are individually hydrogen, or takentogether form a carbon to carbon bond; R₇, R₈ and R₉ are lower alkyl andn is an integer of from 0 to 1; comprising subjecting an opticallyactive isomer of the formula ##STR36## wherein n, A and B are as above;one of R₁ and R₂ is hydrogen and the other is hydroxy, with the provisothat when R₁ is hydroxy, the 2-3 double bond has a cis configuration,and when R₁ is hydrogen, the 2-3 double bond has a transconfiguration;free of other optically active isomers to Claisenrearrangement by reaction under Claisen conditions with a rearrangementagent selected from the group consisting of compounds of the formula:

    CH.sub.2 =CH-OR.sub.10 ##STR37##

wherein R₁₀ is lower alkyl, X is halogen and R₇ and R₈ are as above. 2.The process of claim 1 wherein said optically active isomer is reactedwith a Claisen rearrangement agent of the formula:

    CH.sub.2 =CH-OR.sub.10

wherein R₁₀ is as above.
 3. The process of claim 1 wherein saidoptically active isomer is reacted with a Claisen rearrangement agentselected from the group consisting of compounds of the formula:##STR38## wherein R₇, R₈ and R₁₀ are as above; or mixtures thereof.
 4. Acompound of the formula: ##STR39## wherein R₆ is hydrogen, hydroxy,##STR40## n is an integer from 0 to 1; A and B are individually hydrogenor taken together form a carbon to carbon bond; R₇, R₈ and R₉ are loweralkyl.
 5. The compound of claim 4 wherein said compound is3(S),7-dimethyl-4(trans)-octenoic acid dimethylamide.
 6. The compound ofclaim 4 wherein said compound is 3(S), 7-dimethyl-4(trans)-octenal. 7.The compound of claim 4 wherein said compound is 3(S),7-dimethyl-4(trans)-octenoic acid.
 8. The compound of the formula:##STR41## wherein A and B are individually hydrogen or taken togetherform a carbon to carbon bond, R₆ ' is lower alkoxy and n is an integerof from 0 to
 1. 9. The compound of claim 8 wherein said compound is3(S), 7-dimethyl-4(trans)-octenoic acid ethyl ester.
 10. The compound ofclaim 8 wherein said compound is 3(S), 7(R),11-trimethyl-4(trans),10-dodecadienoic acid ethyl ester.
 11. The processof claim 1 wherein a compound of the formula: ##STR42## wherein n, A andB are as above; and R₆ ' is lower alkoxy, is prepared by treating saidoptically active isomer with a rearrangment agent of the formula:##STR43## wherein R₆ ' is as above.
 12. The process of claim 1 wherein Aand B are hydrogen, R₆ ' is ethoxy and n is
 0. 13. The process of claim11 wherein A and B form a carbon to carbon double bond, R₆ ' is ethoxyand n is 1.